Canonical Wnt Signaling in CD11c+ APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon

Abstract

Aberrant Wnt/β-catenin signaling occurs in several inflammatory diseases, including inflammatory bowel disease and inflammatory bowel disease-associated colon carcinogenesis. However, its role in shaping mucosal immune responses to commensals in the gut remains unknown. In this study, we investigated the importance of canonical Wnt signaling in CD11c⁺ APCs in controlling intestinal inflammation. Using a mouse model of ulcerative colitis, we demonstrated that canonical Wnt signaling in intestinal CD11c⁺ APCs controls intestinal inflammation by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt coreceptors, low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) in CD11c⁺ APCs in LRP5/6^ΔCD11c mice, resulted in enhanced intestinal inflammation with increased histopathological severity of colonic tissue. This was due to microbiota-dependent increased production of proinflammatory cytokines and decreased expression of immune-regulatory factors such as IL-10, retinoic acid, and IDO. Mechanistically, loss of LRP5/6-mediated signaling in CD11c⁺ APCs resulted in altered microflora and T cell homeostasis. Furthermore, our study demonstrates that conditional activation of β-catenin in CD11c⁺ APCs in LRP5/6^ΔCD11c mice resulted in reduced intestinal inflammation with decreased histopathological severity of colonic tissue. These results reveal a mechanism by which intestinal APCs control intestinal inflammation and immune homeostasis via the canonical Wnt-signaling pathway.